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3oof

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==Crystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)benzoic acid==
==Crystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)benzoic acid==
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<StructureSection load='3oof' size='340' side='right' caption='[[3oof]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
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<StructureSection load='3oof' size='340' side='right'caption='[[3oof]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3oof]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OOF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OOF FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3oof]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OOF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OOF FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OOF:4-({(2S)-2-[2-(4-CHLOROPHENYL)-5,6-DIFLUORO-1H-BENZIMIDAZOL-1-YL]-2-CYCLOHEXYLACETYL}AMINO)BENZOIC+ACID'>OOF</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3okh|3okh]], [[3oki|3oki]], [[3olf|3olf]], [[3omm|3omm]], [[3omk|3omk]], [[3ook|3ook]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OOF:4-({(2S)-2-[2-(4-CHLOROPHENYL)-5,6-DIFLUORO-1H-BENZIMIDAZOL-1-YL]-2-CYCLOHEXYLACETYL}AMINO)BENZOIC+ACID'>OOF</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1H4, HCG_20893 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3oof FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oof OCA], [https://pdbe.org/3oof PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oof RCSB], [https://www.ebi.ac.uk/pdbsum/3oof PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oof ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3oof FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oof OCA], [http://pdbe.org/3oof PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3oof RCSB], [http://www.ebi.ac.uk/pdbsum/3oof PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3oof ProSAT]</span></td></tr>
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</table>
</table>
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== Disease ==
 
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[[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
 
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN]] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref> [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref>
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[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acety lamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
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Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.,Richter HG, Benson GM, Bleicher KH, Blum D, Chaput E, Clemann N, Feng S, Gardes C, Grether U, Hartman P, Kuhn B, Martin RE, Plancher JM, Rudolph MG, Schuler F, Taylor S Bioorg Med Chem Lett. 2011 Feb 15;21(4):1134-40. doi: 10.1016/j.bmcl.2010.12.123., Epub 2010 Dec 31. PMID:21269824<ref>PMID:21269824</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3oof" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Bile acid receptor|Bile acid receptor]]
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*[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]]
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*[[Hormone|Hormone]]
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Rudolph, M G]]
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[[Category: Large Structures]]
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[[Category: Bile acid]]
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[[Category: Rudolph MG]]
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[[Category: Cholesterol]]
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[[Category: Coactivator]]
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[[Category: Dna-binding]]
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[[Category: Fxr alternative splicing]]
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[[Category: Hormone receptor]]
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[[Category: Ligand binding domain transcription regulation]]
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[[Category: Nuclear receptor]]
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[[Category: Nucleus]]
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[[Category: Receptor]]
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[[Category: Transcription]]
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Current revision

Crystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)benzoic acid

PDB ID 3oof

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